Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins

Journal of Medicinal Chemistry

Volumn 51, Issue 21, 2008, Pages 6853-6865

  Hay, Michael P ^a   Hicks, Kevin O ^a   Pchalek, Karin ^a,b   Lee, Ho H ^a   Blaser, Adrian ^a   Pruijn, Frederik B ^a   Anderson, Robert F ^a   Shinde, Sujata S ^a   Wilson, William R ^a   Denny, William A ^a  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIN; OXIDE; OXYGEN; TIRAPAZAMINE; TRIAZINE; TRIAZINE DERIVATIVE;

AREA UNDER THE CURVE; ARTICLE; CYTOTOXICITY; DIFFUSION COEFFICIENT; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYPOXIA; IN VITRO STUDY; MOLECULAR MODEL;

CELL HYPOXIA; CELL LINE, TUMOR; CHEMISTRY, PHYSICAL; CYTOTOXINS; ELECTRONS; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; MOLECULAR STRUCTURE; OXIDATION-REDUCTION; OXIDES; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZINES;

EID: 56249100429     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800967h     Document Type: Article

References (69)

1. Semenza, G. L. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J. Bioenerg. Biomembr. 2007, 39, 231-234.
2. Gatenby, R. A.; Gillies, R. J. Glycolysis in cancer: a potential target for therapy. Int. J. Biochem. Cell Biol. 2007, 39, 1358-1366.
3. Harris, A. L. Hypoxia - a key regulatory factor in tumour growth. Nature Rev. Cancer 2002, 2, 38-47.
4. Semenza, G. L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 2002, 8, S62-S67.
5. Pennachietti, S.; Michieli, P.; Galluzzo, M.; Mazzone, M.; Giordano, S.; Comoglio, P. M. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003, 3, 347-361.
6. Cairns, R. A.; Hill, R. P. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004, 64, 2054-2061.
7. Subarsky, P.; Hill, R. P. The hypoxic tumour microenvironment and metastatic progression. Clin. Exp. Metastases 2003, 20, 237-250.
8. Durand, R. E. The influence of microenvironmental factors during cancer therapy. In Vivo 1994, 8, 691-702.
9. Tannock, I. F. Conventional cancer therapy: promise broken or promise delayed? Lancet 1998, 351, 9-16.
10. Brown, J. M.; Wilson, W. R. Exploiting tumor hypoxia in cancer treatment. Nature Rev. Cancer 2004, 4, 437-447.
11. Nordsmark, M.; Overgaard, M.; Overgaard, J. Pretreatment oxygen-ation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 1996, 41, 31-39.
12. Fyles, A. W.; Milosevic, M.; Wong, R.; Kavanagh, M. C.; Pintilie, M.; Sun, A.; Chapman, W.; Levin, W.; Manchul, L.; Keane, T. J.; Hill, R. P. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother. Oncol. 1998, 48, 149-156.
13. Koukourakis, M. I.; Bentzen, S. M.; Giatromanolaki, A.; Wilson, G. D.; Daley, F. M.; Saunders, M. I.; Dische, S.; Sivridis, E.; Harris, A. L. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J. Clin. Oncol. 2006, 24, 727-735.
14. Denny, W. A.; Wilson, W. R.; Hay, M. P. Recent developments in the design of bioreductive drugs. Br. J. Cancer 1996, 74, S32-S38.
15. Brown, J. M.; Giaccia, A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998, 58, 1408-1416.
16. Brown, J. M. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br. J. Cancer 1993, 67, 1163-1170.
17. Denny, W. A.; Wilson, W. R. Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia. Expert Opin. Invest. Drugs 2000, 9, 2889-2901.
18. Patterson, A. V.; Saunders, M. P.; Chinje, E. C.; Patterson, L. H.; Stratford, I. J. Enzymology of tirapazamine metabolism: a review. Anti-Cancer Drug Des. 1998, 13, 541-573.
19. Anderson, R. F.; Shinde, S. S.; Hay, M. P.; Gamage, S. A.; Denny, W. A. Activation of 3-amino-1,2,4-benzotriazine 1,4-dioxide antitumor agents to oxidizing species following their one-electron reduction. J. Am. Chem. Soc. 2003, 125, 748-756.
20. Shinde, S. S.; Anderson, R. F.; Hay, M. P.; Gamage, S. A.; Denny, W. A. Oxidation of 2-deoxyribose by benzotriazinyl radicals of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides. J. Am. Chem. Soc. 2004, 126, 7853-7864.
21. Daniels, J. S.; Gates, K. S. DNA cleavage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR4233). Evidence for involvement of hydroxyl radical. J. Am. Chem. Soc. 1996, 118, 3380-3385.
22. 2. J. Am. Chem. Soc. 2007, 129, 12870-12877.
23. Wang, J.; Biedermann, K. A.; Brown, J. M. Repair of DNA and chromosome breaks in cells exposed to SR 4233 under hypoxia or to ionizing radiation. Cancer Res. 1992, 52, 4473-4477.
24. Siim, B. G.; van Zijl, P. L.; Brown, J. M. Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro. Br. J. Cancer 1996, 73, 952-960.
25. Siim, B. G.; Menke, D. R.; Dorie, M. J.; Brown, J. M. Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia. Cancer Res. 1997, 57, 2922-2928.
26. Peters, K. B.; Brown, J. M. Tirapazamine: A Hypoxia-Activated Topoisomerase II Poison. Cancer Res. 2002, 62, 5248-5253.
27. Evans, J. W.; Chernikova, S. B.; Kachnic, L. A.; Banath, J. P.; Sordet, O.; Delahoussaye, Y. M.; Treszezamsky, A.; Chon, B. H.; Feng, Z.; Gu, Y.; Wilson, W. R.; Pommier, Y.; Olive, P. L.; Powell, S. N.; Btown, J. M. Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Res. 2008, 68, 257-265.
28. Brown, J. M.; Lemmon, M. J. Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res. 1990, 50, 7745-7459.
29. Brown, J. M.; Lemmon, M. J. Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Int. J. Radiat. Oncol., Biol., Phys. 1991, 20, 457-461.
30. Dorie, M. J.; Brown, J. M. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res. 1993, 53, 4633-4636.
31. Dorie, M. J.; Brown, J. M. Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother. Pharmacol. 1997, 39, 361-366.
32. Marcu, L.; Olver, I. Tirapazamine: From Bench to Clinical Trials. Curr. Clin. Pharmacol. 2006, 1, 71-79.
33. Rischin, D.; Fisher, R.; Peters, L.; Corry, J.; Hicks, R. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography and hypoxic cytotoxins. Int. J. Radiat. Oncol., Biol., Phys. 2007, 69, S61-S63.
34. Rischin, D.; Peters, L.; O'Sullivan, B.; Giralt, J.; Yuen, K.; Trotti, A.; Bernier, J.; Bourhis, J.; Henke, M.; Fisher, R. Phase III study of tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck. J. Clin. Oncol. 2008, 26, abstract LBA6008.
35. Rischin, D.; Hicks, R. J.; Fisher, R.; Binns, D.; Corry, J.; Porceddu, S.; Peters, L. J. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of TransTasman Radiation Oncology Group Study 98.02. J. Clin. Oncol. 2006, 24, 2098-2104.
36. Peters, L.; Rischin, D.; Fisher, R.; Corry, J.; Hicks, R. Identification and therapeutic targeting of hypoxia in H&N cancer. Int. Congr. Radiat. Res. 2007,
37. Rischin, D.; Peters, L.; Fisher, R.; Macann, A.; Denham, J.; Poulsen, M.; Jackson, M.; Kenny, L.; Penniment, M.; Corry, J.; Lamb, D.; McClure, B. Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J. Clin. Oncol. 2005, 23, 79-87.
38. Durand, R. E.; Olive, P. L. Physiologic and cytotoxic effects of tirapazamine in tumor-bearing mice. Radiat. Oncol. Invest. 1997, 5, 213-219.
39. Durand, R. E.; Olive, P. L. Evaluation of bioreductive drugs in multicell spheroids. Int. J. Radiat. Oncol, Biol., Phys. 1992, 22, 689-692.
40. Hicks, K. O.; Fleming, Y.; Siim, B. G.; Koch, C. J.; Wilson, W. R. Extravascular diffusion of tirapazamine: effect of metabolic consumption assessed using the multicellular layer model. Int. J. Radiat. Oncol., Biol., Phys. 1998, 42, 641-649.
41. Kyle, A. H.; Minchinton, A. I. Measurement of delivery and metabolism of tirapazamine to tumour tissue using the multilayered cell culture model. Cancer Chemother. Pharmacol. 1999, 43, 213-220.
42. Baguley, B. C.; Hicks, K. O.; Wilson, W. R. Tumour cell cultures in drug development. In Anticancer Drug Development; Baguley, B.C.; Kerr, D. J., Eds.; Academic Press: San Diego, 2002; pp 269-284.
43. Hicks, K. O.; Pruijn, F. B.; Sturman, J. R.; Denny, W. A.; Wilson, W. R. Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in multicellular layers. Cancer Res. 2003, 63, 5970-5977.
44. Hicks, K. O.; Siim, B. G.; Pruijn, F. B.; Wilson, W. R. Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat. Res. 2004, 161, 656-666.
45. Hicks, K. O.; Pruijn, F. B.; Secomb, T. W.; Hay, M. P.; Hsu, R.; Brown, J. M.; Denny, W. A.; Dewhirst, M. W.; Wilson, W. R. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J. Natl. Cancer Inst. 2006, 98, 1118-1128.
46. Hicks, K. O.; Myint, H.; Patterson, A. V.; Pruijn, F. B.; Siim, B. G.; Patel, K.; Wilson, W. R. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int. J. Radiat. Oncol., Biol., Phys. 2007, 69, 560-571.
47. Pruijn, F. B.; Sturman, J.; Liyanage, S.; Hicks, K. O.; Hay, M. P.; Wilson, W. R. Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures. J. Med. Chem. 2005, 48, 1079-1087.
48. Hay, M. P.; Hicks, K. O.; Pruijn, F. B.; Pchalek, K.; Siim, B. G.; Wilson, W. R.; Denny, W. A. Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport. J. Med. Chem. 2007, 50, 6392-6404.
49. Hay, M. P.; Pchalek, K.; Pmijn, F. B.; Hicks, K. O.; Siim, B. G.; Anderson, R. R.; Shinde, S. S.; Phillips, V.; Denny, W. A.; Wilson, W. R. Hypoxia-selective 3-alkyl 1,2,4-benzotriazine 1,4-dioxides: the influence of hydrogen bond donors on extravascular transport and antitumor activity. J. Med. Chem. 2007, 50, 6654-6664.
50. Hay, M. P.; Gamage, S. A.; Kovacs, M. S.; Pruijn, F. B.; Anderson, R. F.; Patterson, A. V.; Wilson, W. R.; Brown, J. M.; Denny, W. A. Structure-activity relationships of 1,2,4-benzotriazine 1,4-dioxides as hypoxia-selective analogues of tirapazamine. J. Med. Chem. 2003, 46, 169-182.
51. Zeman, E. M.; Baker, M. A.; Lemmon, M. J.; Pearson, C. I.; Adams, J. A.; Brown, J. M.; Lee, W. W.; Tracy, M. Structure-activity relationships for benzotriazine di-N-oxides. Int. J. Radiat. Oncol., Biol., Phys. 1989, 16, 977-981.
52. Minchinton, A. I.; Lemmon, M. J.; Tracy, M.; Pollart, D. J.; Martinez, A. P.; Tosto, L. M.; Brown, J. M. Second-generation 1,2,4-benzotriazine 1,4-di-N-oxide bioreductive antitumor agents: pharmacology and activity in vitro and in vivo. Int. J. Radiat. Oncol., Biol., Phys 1992, 22, 701-705.
53. Kelson, A. B.; McNamara, J. P.; Pandey, A.; Ryan, K. J.; Dorie, M. J.; McAfee, P. A.; Menke, D. R.; Brown, J. M.; Tracy, M. 1,2,4-Benzotriazine 1,4-dioxides. An important class of hypoxic cytotoxins with antitumor activity. Anti-Cancer Drug Des. 1998, 13, 575-592.
54. Jiang, F.; Yang, B.; Fan, L.; Heb, Q.; Hu, Y. Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives. Bioorg. Med. Chem. Lett. 2006, 16, 4209-4213.
55. Jiang, F.; Weng, Q.; Sheng, R.; Xia, Q.; He, Q.; Yang, B.; Hu, Y. Synthesis, structure and hypoxic cytotoxicity of 3-amino-1,2,4-benzotriazine-1, 4-dioxide derivatives. Arch. Pharm. (Weinheim, Ger.) 2007, 340, 258-263.
56. Cerecetto, H.; Gonzalez, M.; Onetto, S.; Saenz, P.; Ezpeleta, O.; De Cerain, A. L.; Monge, A. 1,2,4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part II. Arch. Pharm. (Weinheim, Ger.) 2004, 337, 247-258.
57. Cerecetto, H.; Gonzalez, M.; Risso, M.; Saenz, P.; Olea-Azar, C.; Bruno, A. M.; Azqueta, A.; De Cerain, A. L.; Monge, A. 1,2,4-Triazine N-oxide derivatives: Studies as potential hypoxic cytotoxins. Part III. Arch. Pharm. (Weinheim, Ger.) 2004, 337, 271-280.
58. Monge, A.; Palop, J. A.; Gonzalez, M.; Martinez-Crespo, F. J.; De Cerain, A. L.; Sainz, Y.; Narro, S.; Barker, A. J.; Hamilton, E. New hypoxia-selective cytotoxins derived from quinoxaline 1,4-dioxides. J. Hetercycl. Chem. 1995, 32, 1213-1217.
59. Monge, A.; Palop, J. A.; De Cerain, A. L.; Senador, V.; Martinez-Crespo, F. J.; Sainz, Y.; Narro, S.; Garcia, E.; de Miguel, C.; Gonzalez, M. Hypoxia-selective agents derived from quinoxaline 1,4-di-N-oxides. J. Med. Chem. 1995, 38, 1786-1792.
60. Monge, A.; Martinez-Crespo, F. J.; De Cerain, A. L.; Palop, J. A.; Narro, S.; Senador, V.; Marin, A.; Sainz, Y.; Gonzalez, M.; Hamilton, E. Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N-oxides. 2. J. Med. Chem. 1995, 38, 4488-4494.
61. Amin, K. M.; Ismail, M. M. F.; Noaman, E.; Soliman, D. H.; Ammard, Y. A. New quinoxaline 1,4-di-N-oxides, Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1,4-di-N-oxides. Bioorg. Med. Chem. 2006, 14, 6917-6923.
62. Hay, M. P.; Denny, W. A. A new and versatile synthesis of 3-alkyl-1,2,4-benzotriazine-1,4-dioxides: preparation of the bioreductive cytotoxins SR4895 and SR4941. Tetrahedron Lett. 2002, 43, 9569-9571.
63. Pchalek, K.; Hay, M. P. Stille Coupling Reactions in the Synthesis of Hypoxia-Selective 3-Alkyl-1,2,4-Benzotriazine 1,4-Dioxide Anticancer Agents. J. Org. Chem. 2006, 71, 6530-6535.
64. Anderson, R. F.; Denny, W. A.; Li, W.; Packer, J. E.; Tercel, M.; Wilson, W. R. Pulse radiolysis studies on the fragmentation of arylmethyl quaternary nitrogen mustards upon their one-electron reduction in aqueous solution. J. Phys. Chem. A 1997, 101, 9704-9709.
65. Wardman, P. Reduction potentials of one-electron couples involving free radicals in aqueous solution. J. Phys. Chem. Ref. Data 1989, 18, 1637-1755.
66. Siim, B. G.; Hicks, K. O.; Pullen, S. M.; van Zijl, P. L.; Denny, W. A.; Wilson, W. R. Comparison of aromatic and tertiary amine N-oxides of acridine DNA intercalators as bioreductive drugs - cytotoxicity, DNA binding, cellular uptake, and metabolism. Biochem. Pharmacol. 2000, 60, 969-978.
67. Pruijn, F. B.; Patel, K.; Hay, M. P.; Wilson, W. R.; Hicks, K. O. Prediction of Tumour Tissue Diffusion Coefficients of Hypoxia-Activated Prodrugs from Physicochemical Parameters. Aust. J. Chem. 2008, 61, 687-693.
68. Wang, M.; Roberts, D. L.; Paschke, R.; Shea, T. M.; Masters, B. S. S.; Kim, J-J. P. Three-dimensional structure of NADPH-cytochrome P450reductase: prototype for FMN- and FAD-containing enzymes. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 8411-8416.
69. Zhao, Q.; Modi, S.; Smith, G.; Paine, M.; Mcdonagh, P. D.; Wolf, C. R.; Tew, D.; Lian, L.Y.; Roberts, G. C. K.; Driessen, H. P. C. Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 Å resolution. Protein Sci. 1999, 8, 298-306.